美国圣路易斯华盛顿大学Brian J. DeBosch研究团队发现，肝细胞精氨酸酶2对三羧酸循环的层级调控将尿素循环与氧化代谢联系起来。该项研究成果于2024年8月7日在线发表在《细胞—代谢》上。

研究人员生成了肝细胞特异性精氨酸酶2缺失的小鼠（Arg2^LKO），揭示了轻微的补偿性尿素循环缺陷。稳定同位素追踪和呼吸测定显示，肝细胞尿素和三羧酸循环（TCA）通量缺陷，线粒体氧化代谢受损，谷氨酰胺再生作用受损，尽管在早期成年期能量和葡萄糖稳态正常。

然而，在中年期，喂以标准饮食和高脂饮食的Arg2^LKO小鼠发展为加重的葡萄糖和脂质紊乱，这些紊乱通过替换TCA循环氧化底物烟酰胺腺嘌呤二核苷酸可逆转。

此外，基于血清的尿素、TCA循环和线粒体紊乱标志物可以预测106606名患者近十年的纤维炎症性肝病发生。这些数据揭示了通过ARG2驱动的尿素-TCA的层级调控对氧化代谢的重要作用。此外，这一回路的扰动可能因果地将尿素循环损害与纤维炎症性肝病联系起来。

据介绍，尿素循环损害及其与肥胖和炎症的关系一直不清楚，部分原因是经典尿素循环缺陷的临床表现非常显著。

附：英文原文

Title: Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism

Author: Yiming Zhang, Cassandra B. Higgins, Stefani Tica, Joshua A. Adams, Jiameng Sun, Shannon C. Kelly, Xiaoyu Zong, Dennis J. Dietzen, Terri Pietka, Samuel J. Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J. DeBosch

Issue&Volume: 2024-08-07

Abstract: Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

DOI: 10.1016/j.cmet.2024.07.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00278-X